The Chileans have fallen into South America's secondary competition after finishing third in their Copa Libertadores group, while America Mineiro came second in Group F.
Match preview
Having lifted the Chilean Primera Division for the 33rd time in the club's history last season, reclaiming their domestic title for the first time since 2017, Colo-Colo would have been hoping to make a major impact in the Copa Libertadores.
However, six points from six games was not enough for them to progress into the knockout stages, but Gustavo Quinteros's side will receive a second bite at the cherry having dropped down into the Copa Sudamericana.
Los Albos have never won this competition, with their best effort being when losing to Pachuca in the 2006 final, so they will be keen to make the most of the golden opportunity which they have been provided with.
Having beaten Union La Calera 6-1 in their domestic cup in their most recent match, Quinteros and his players should be full of confidence of securing a positive result from the first leg at Estadio Monumental David Arellano on Tuesday.
America Mineiro, meanwhile, are embarking on their debut Copa Sudamericana campaign, having also competed in the Copa Libertadores for the first time in their history last season.
Coelho crashed out of the group stage without a victory to their name in that competition, but they have found life a little easier in the step blow, edging out Millonarios on goal difference to reach the knockout stages.
On a dramatic final matchday, late goals from Danilo Avelar and Juninho helped their side come from behind to defeat Penarol 2-1, with Defensa y Justicia's 3-1 victory against the Colombians seeing their opponents crash out by one goal.
With his side sitting rock-bottom in Brazil's Serie A, and therefore staring down the barrel at a third relegation in eight years, Vagner Mancini will be hoping his players can make the most of their continental adventure. They must remain in the tie before their home leg next week.
Colo-Colo Copa Sudamericana form:
Colo-Colo form (all competitions):
D
W
L
D
L
D
America Mineiro Copa Sudamericana form:
W
L
D
L
W
W
America Mineiro form (all competitions):
L
L
W
D
W
L
Team News
Colo-Colo will have Maximiliano Falcon and Esteban Pavez available, with their suspensions only applying to domestic competitions.
Brayan Cortes and Leonardo Gil could come into the hosts' starting XI after being named on the bench for their side's cup thrashing last week, but otherwise Quinteros is unlikely to make many changes.
Mancini, meanwhile, must combat potential fatigue among his ranks given that they face Corinthians in the second leg of their Copa do Brasil quarter-final clash on Saturday, having been beaten 3-1 by Coritiba three days prior to this clash.
However, Mikael, Ricardo Silva, Dada Belmonte and Adyson are all expected to remain sidelined by injury, but Nicolas should be fit enough to start at left-back.
Colo-Colo possible starting lineup:
Cortes; Wiemberg, Falcon, Saldivia; Rojas, Pizarro, Pavez, Bouzat; Gil, Palacios; Lezcano
America Mineiro possible starting lineup:
Pasinato; Lopes, Eder, Maidana, Nicolas; Everaldo, Juninho, Martinez, Kal, Pedrinho; Henrique
We say: Colo-Colo 2-0 America Mineiro
Colo-Colo should be the fresher team given that their domestic season has been paused since mid-May, and we can envisage them using this factor and home advantage to help them secure a healthy first-leg lead.
After two respectable mid-table finishes in Brazil, America Mineiro have been disappointing this time around, with another relegation battle looking set to be on the cards. They face an uphill battle here.